AU2009227081A1 - Crystalline forms of dimethoxy docetaxel and methods for preparing same - Google Patents
Crystalline forms of dimethoxy docetaxel and methods for preparing same Download PDFInfo
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- AU2009227081A1 AU2009227081A1 AU2009227081A AU2009227081A AU2009227081A1 AU 2009227081 A1 AU2009227081 A1 AU 2009227081A1 AU 2009227081 A AU2009227081 A AU 2009227081A AU 2009227081 A AU2009227081 A AU 2009227081A AU 2009227081 A1 AU2009227081 A1 AU 2009227081A1
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- hydroxy
- dimethoxy
- oxotax
- acetoxy
- tert
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- 238000000034 method Methods 0.000 title claims description 15
- -1 dimethoxy docetaxel Chemical compound 0.000 title claims description 4
- 229960003668 docetaxel Drugs 0.000 title description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 26
- 238000010586 diagram Methods 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 7
- 230000035800 maturation Effects 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000010408 sweeping Methods 0.000 claims description 6
- ZVAFCKLQJCZGAP-WDEREUQCSA-N (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-WDEREUQCSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical group CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 229940068968 polysorbate 80 Drugs 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims 11
- 239000004593 Epoxy Substances 0.000 claims 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005102 attenuated total reflection Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- ZVAFCKLQJCZGAP-UHFFFAOYSA-N 2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- VOXXWSYKYCBWHO-UHFFFAOYSA-N 3-phenyllactic acid Chemical compound OC(=O)C(O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 150000004683 dihydrates Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
WO 2009/115655 PCT/FR2009/000042 1 CRYSTALLINE FORMS OF DIMETHOXY DOCETAXEL AND METHODS FOR PREPARING THE SAME The present invention relates to crystalline forms of dimethoxy docetaxel or 4 -acetoxy-2a-benzoyloxy-5p,20-epoxy-1 -hydroxy-7p,1Op-dimethoxy-9-oxotax 5 11-en-13ac-yl (2R,3S)- 3 -tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and to methods for the preparation thereof. 4 -Acetoxy-2a-benzoyloxy-5p,20-epoxy-1-hydroxy-7p,10p-dimethoxy 9-oxotax- I -en-I3a-yl ( 2
R,
3 S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl propionate exhibits notable anticancer and antileukaemic properties. 10 4 -Acetoxy-2at-benzoyloxy-5p,20-epoxy-1-hydroxy-7,10(p-dimethoxy 9-oxotax- 11-en-13a-yl (2R,3 S)-3 -tert-butoxycarbonylamino-2-hydroxy-3-phenyl propionate is prepared according to the method which is described more particularly in PCT International Application WO 96/30355 or PCT International Application WO 99/25704. According to the method described in these applications, the product 15 is not crystallized and is not characterized. It was found that the acetone solvate of 4-acetoxy-2a-benzoyloxy-5p,20 epoxy-1 -hydroxy-7p, 10p -dimethoxy-9-oxotax- 11-en- 13a-yl (2R,3S)-3-tert-butoxy carbonylamino-2-hydroxy-3-phenylpropionate (called form A) was completely determined and characterized according to the patent published under number 20 W02005/028462. The present invention relates to new crystalline forms, with the exclusion of the acetonate form, the only one known to date. According to the present invention, it has now been found that certain anhydrous forms, certain ethanolic solvates or heterosolvates and hydrated forms have 25 been completely characterized from a physical and chemical structure point of view. According to the invention, among the anhydrous forms of 4-acetoxy-2az benzoyloxy-5p,20-epoxy-1-hydroxy-7,10p-dimethoxy-9-oxotax-l 1-en-I 3a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, five different forms have been identified, among the ethanolic solvates or heterosolvates of 30 4 -acetoxy-2a-benzoyloxy-5 ,20-epoxy- 1 -hydroxy-7p,1 0p-dimethoxy-9-oxotax 11-en- 13 a-yl (2R,3S)- 3 -tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, four different forms have been identified and among the hydrates of 4-acetoxy-2a benzoyloxy-5p,20-epoxy-1 -hydroxy-7p,10p-dimethoxy-9-oxotax-l l-en- 1 3a-yl WO 2009/115655' PCT/FR2009/000042 2
(
2
R,
3
S)-
3 -tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, two different forms have been identified. The five anhydrous forms identified were obtained according to the following methods: 5 - The anhydrous form B by a method which consists in heating the acetone form or form A obtained according to the patent mentioned above, between 100 and 110 0 C under vacuum or nitrogen sweeping. This treatment is preferably carried out for at least 9 hours before a return to ambient temperature without inducing chemical decomposition. Its melting point by DSC is approximately 10 150'C. The PXRD diagram of the anhydrous form B exhibits characteristic lines located at 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1, 14.3, 15.4 and 15.9 ± 0.2 degrees 2-theta. - The anhydrous form C is obtained by maturation of the acetone solvate form A, or of the anhydrous form B, in water followed by drying at up to 50'C 15 and maintaining between 0 and 5% RH at ambient temperature. Its melting point by DSC is approximately 146 0 C. The PXRD diagram of the anhydrous form C exhibits characteristic lines located at 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and 13.1 ± 0.2 degrees 2-theta. It is, among the various anhydrous forms, the least stable of all the forms described in the present 20 invention. In the presence of a relative humidity of greater than 5%, it changes to a hydrated form. - The anhydrous form D is obtained according to a first method by crystallization of the form A in an oil (especially Miglyol), following by rinsing with an alkane, for example heptane; the second preparation method 25 consists in leaving a solution of 4-acetoxy-2c-benzoyloxy-5p,20-epoxy-1 hydroxy-7p ,10 -dimethoxy-9-oxotax- 11-en- 13 at-yl (2R,3S)-3-tert butoxycarbonylamino-2-hydroxy-3-phenylpropionate in a mixture of Polysorbate 80, pH 3.5, ethanol and water (preferably a 25/25/50 mixture) to crystallize for approximately 48 hours. Its boiling point by DSC is 30 approximately 175 0 C (cf Figure 1) and is found to be the highest of all the anhydrous forms isolated. The PXRD diagram of the anhydrous form D (cf Figure 2) exhibits characteristic lines located at 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6, 10.8, 11.1 and 12.3 ± 0.2 degrees 2-theta. The FTIR spectrum of the anhydrous form D exhibits characteristic bands located at 979, 1072, 1096, 35 1249, 1488, 1716, 1747, 3436 I cm- (cf Figure 3). Among all the forms WO 2009/115655
-
PCFR200/000042 3 described in the present invention, it is the most stable anhydrous form. - The anhydrous form E is obtained at ambient temperature by maturation of the acetone form or form A in ethanol so as to intermediately form an ethanolic form which is subsequently desolvated under nitrogen sweeping or by heating 5 at approximately 100 0 C for 2 hours. Its melting point by DSC is approximately 157*C. The PXRD diagram of the anhydrous form E exhibits characteristic lines located at 7.1, 8.1, 8.9, 10.2, 10.8, 12.5, 12.7, 13.2, 13.4 and 13.9 ± 0.2 degrees 2-theta. - The anhydrous form F is obtained by desolvating the ethanol/water 10 heterosolvate at 120*C under a nitrogen atmosphere for 24 hours and then maintaining in a dry environment at 0% RH at ambient temperature. Its melting point by DSC is approximately 148 0 C. The PXRD diagram of the anhydrous form F exhibits characteristic lines located at 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3 ± 0.2 degrees 2-theta. 15 There are four crystalline forms identified in ethanolic solvate or heterosolvate form: - The ethanolate form B is obtained at ambient temperature by maintaining the anhydrous form B in an ethanol-vapour-saturated environment. The PXRD 20 diagram of the ethanolate form B exhibits characteristic lines located at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9, 13.4, 14.2, 14.7 and 15.1 ± 0.2 degrees 2-theta. - The ethanolate form D is obtained at ambient temperature by maintaining the anhydrous form D in an ethanol-vapour-saturated environment. The PXRD diagram of the ethanolate form D (cf Figure 4) exhibits characteristic lines 25 located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5, 11.1, 11.5 and 11.9 ± 0.2 degrees 2-theta. - The ethanolate form E is obtained at ambient temperature by maturation of the acetonate form A in ethanol. The PXRD diagram of the ethanolate form E (cf Figure 5) exhibits characteristic lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5, 30 13.2, 13.4, 13.9 and 14.2 ± 0.2 degrees 2-theta. - The ethanol/water heterosolvate form F is obtained by maintaining the form B in a minimum amount of ethanol at reflux, slow cooling and isolation at ambient temperature and ambient relative humidity. The PXRD diagram of the ethanol/water heterosolvate form F exhibits characteristic lines located at 0 2009/1156is~ - 'PC iR2409/000042 4 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3, 10.9, 11.2 and 12.2 0.2 degrees 2-theta. There are two crystalline forms identified in hydrate form: - The monohydrated forms C are obtained at ambient temperature by 5 maintaining the anhydrous form C in an atmosphere containing at least 10% relative humidity. The PXRD diagram of the monohydrate form C exhibits characteristic lines located at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1, 11.9, 12.2, 12.6 and 13.3 + 0.2 degrees 2-theta. - The dihydrate form C is obtained at ambient temperature by maintaining the 10 anhydrous form C in an atmosphere containing at least 60% relative humidity. The PXRD diagram of the dehydrate form C exhibits characteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7, 12.3, 12.6 and 13.2 ± 0.2 degrees 2-theta. Other, nonethanolic, solvates of the form B were prepared, such as in particular those obtained with the following solvents: dichloromethane, diisopropyl 15 ether, n-propanol, isopropanol, toluene, methyl isobutyl ketone, tetrahydrofuran, dimethylformamide, ethyl acetate, etc. The present invention will be described more fully by means of the following examples which should not be considered to limit the invention. Experimental analysis conditions: 20 Differential Scanning Calorimetry (DSC): The measurements were carried out on a T.A. Instruments DSC2010 thermal analyser. The sample is subjected to temperature programming from 25 0 C to 225 0 C with a 25 heating rate of 5 0 C/min. The product is placed in a crimped aluminium capsule and the amount of product analysed is between 2 and 5 mg. Constant nitrogen sweeping at 55 mL/min is used in the oven chamber. 30 Powder X-Ray Diffraction (PXRD): WG 2009/Y1S655 -. PCT/FR2009/000042 5 The analyses were carried out on a Panalytical X'Pert Pro diffractometer with a reflection-mode Bragg-Brentano focusing geometry (0-20) assembly. The product analysed is deposited as a thin layer on a silicon single crystal. A copper anticathode tube (45 kV/40 mA) supplies an incident radiation Cu Kal (k = 1.5406 A). The beam 5 is collimated using Sollers slits which improve the parallelism and variable slits which limit scattering. An X'Celerator detector completes the device. The diagram recording characteristics are the following: sweeping from 2 to 30 degrees 20, counting time from 100 to 500 seconds per step with a step of 0.017'. 10 Fourier Transform InfraRed (FTIR) spectrometry: The solid samples were analysed using a Nicolet Nexus spectrometer. The analysis is carried out by attenuated total reflectance (ATR) using a Smart Orbit accessory from 15 the company Therno (single reflection diamond crystal ATR accessory). The spectral range swept is between 4000 and 400 cm- 1 with a resolution of 2 cm- 1 and an accumulated scan number of 20. Example 1 20 Two tests of dissolution of approximately 550 mg of 4-acetoxy-2a benzoyloxy-5p,20-epoxy-1-hydroxy-7p,10p-dimethoxy-9-oxotax-l 1-en-13a-yl
(
2
R,
3
S)-
3 -tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 14 g of Miglyol 812 Neutral oil, Sasol are carried out. Magnetic stirring is carried out at 500 rpm for 24 hours at ambient temperature. 25 After one week, the samples are vacuum-filtered and rinsed with heptane. Each sample is analysed by PXRD for confirmation of the form obtained. After filtration, between 300 and 350 mg of anhydrous form D are obtained. Example 2 Approximately 3 g of 4 -acetoxy-2a-benzoyloxy-5p,20-epoxy-1-hydroxy 30 7P,10f-dimethoxy-9-oxotax- 11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino- WO~2009/115655 Y' CT/FR2009/000042 6 2 -hydroxy-3-phenylpropionate are dissolved in a mixture of 50 mL ethanol + 50 mL Polysorbate 80, pH 3.5. 100 mL of water are added to the previous mixture and the whole is homogenized. After storage for 48 hours at ambient temperature, crystals of anhydrous form D appeared. The amount of crystallized product recovered by 5 filtration is approximately 2.45 g. A comparative stability study was carried out between the acetone solvate form A and the anhydrous form D. The comparison of the PXRD analyses carried out on the A and D forms immediately after production and after having maintained said forms at 40'C for one month gives the following results: 10 - Form A: partial desolvation resulting in a mixture of the acetone solvate form A and of the anhydrous form B being obtained. - Form D: no change detected after maintaining at 40'C for one month.
Claims (10)
1. - Crystalline forms of 4 -acetoxy-2a-benzoyloxy-5p,20-epoxy-1-hydroxy 7J,100-dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino 2 -hydroxy-3-phenylpropionate, with the exception of the acetonate form. 5 2. - Forms according to Claim 1, characterized in that they are anhydrous forms of 4 -acetoxy-2a-benzoyloxy-5p,20-epoxy-1-hydroxy-7p,10p-dimethoxy
9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl propionate. 3. - Anhydrous form B of 4-acetoxy-2c-benzoyloxy-5p,20-epoxy-1 10 hydroxy-7p,10p-dimethoxy-9-oxotax-11-en-13c-yI (2R,3 S)-3 -tert-butoxycarbonyl amino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting characteristic lines located at 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1,
14.3, 15.4 and 15.9 ± 0.2 degrees 2-theta. 4. - Anhydrous form C of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-1 15 hydroxy-7p,I0p-dimethoxy-9-oxotax-l1-en-13a-y (2R,3S)-3-tert-butoxycarbonyl amino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting characteristic lines located at 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and 13.1 ± 0.2 degrees 2-theta. 5. - Anhydrous form D of 4-acetoxy-2x-benzoyloxy-5p,20-epoxy-1 20 hydroxy-75,1 Op-dimethoxy-9-oxotax- 11-en-13a.-yl (2R,3S)-3-tert-butoxycarbonyl amino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting characteristic lines located at 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6, 10.8, 11.1 and 12.3 ± 0.2 degrees 2-theta. 6. - Anhydrous form E of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-l 25 hydroxy-7p,1O-dimethoxy-9-oxotax- 11-en-13a-yl (2R,3S)-3-tert-butoxycarbonyl amino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting characteristic lines located at 7.1, 8.1, 8.9, 10.2, 10.8, 12.5, 12.7, 13.2, 13.4 and 13.9 0.2 degrees 2-theta. 7. - Anhydrous form F of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-1 30 hydroxy-7p,10p-dimethoxy-9-oxotax- 11-en-13ac-yl (2R,3S)-3-tert-butoxycarbonyl amino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD WO 2OI9115655 PCT/FR2009/G0o42 diagram exhibiting characteristic lines located at 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3 ± 0.2 degrees 2-theta. 8. - Forms according to Claim 1, characterized in that they are ethanolic solvate or heterosolvate forms of 4-acetoxy-2a-benzoyloxy-5 P,20-epoxy-1-hydroxy 5 7p,1 0J-dimethoxy-9-oxotax- 11-en- 13a-yl (2R,3 S)-3-tert-butoxycarbonylamino 2 -hydroxy-3-phenylpropionate. 9. - Ethanolate form B of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-1 -hydroxy 7p, 1 01-dimethoxy-9-oxotax- 11-en- 13a-yl (2R,3 S)-3-tert-butoxycarbonylamino 2 -hydroxy-3-phenylpropionate according to Claim 8, characterized by a PXRD 10 diagram exhibiting characteristic lines located at 7.3, 7.8, 8.8, 10,2, 12.6, 12.9, 13.4, 14.2, 14.7 and 15.1 ± 0.2 degrees 2-theta. 10. - Ethanolate form D of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy 1-hydroxy-70,10p-dimethoxy-9-oxotax-11-en-13a-y1 (2R,3S)-3-tert-butoxycarbonyl anino- 2 -hydroxy-3-phenylpropionate according to Claim 8, characterized by a PXRD 15 diagram exhibiting characteristic lines located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5, 11.1, 11.5 and 11.9 0.2 degrees 2-theta. 11. -- Ethanolate form E of 4 -acetoxy-2a-benzoyloxy-5P,20-epoxy 1-hydroxy-76,10p-dimethoxy-9-oxotax-11-en-13t-yI (2R,3S)-3-tert-butoxycarbonyl amino- 2 -hydroxy-3-phenylpropionate according to Claim 8, characterized by a PXRD 20 diagram exhibiting characteristic lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5, 13.2, 13.4, 13.9 and 14.2 ± 0.2 degrees 2-theta. 12. - Ethanol/water heterosolvate form F of 4-acetoxy-2ax-benzoyloxy 5p,20-epoxy-1-hydroxy-7p,100-dimethoxy-9-oxotax- 11-en-13a-yl (2R,3S)-3-tert butoxycarbonylamino-2-hydroxy-3-phenylpropionate according to Claim 8, 25 characterized by a PXRD diagram exhibiting characteristic lines located at 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3, 10.9, 11.2 and 12.2 + 0.2 degrees 2-theta. 13. - Forms according to Claim 1, characterized in that they are hydrate forms of 4 -acetoxy-2ct-benzoyloxy-5p,20-epoxy-i-hydroxy-7p,10p-dimethoxy 9-oxotax- 11-en- 13 a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl 30 propionate. 14. - Monohydrate form C of 4-acetoxy-2x-benzoyloxy-5p,20-epoxy 1-hydroxy-70,10p-dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonyl amino-2-hydroxy-3-phenylpropionate according to Claim 13, characterized by a O 2009i115655 PCif/FR2009/000042 9 PXRD diagram exhibiting characteristic lines located at 4.3, 6.8, 7.4, 8,6, 10.1, 11.1, 11.9, 12.2, 12.6 and 13.3 ± 0.2 degrees 2-theta.
15. - Dihydrate form C of 4-acetoxy-2a-benzoy1oxy-5p,20-epoxy 5 1-hydroxy-7p,10p-dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonyl amino-2-hydroxy-3-phenylpropionate according to Claim 13, characterized by a PXRD diagram exhibiting characteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7, 12.3, 12.6 and 13.2 ± 0.2 degrees 2-theta.
16. - Method for preparing the anhydrous form B according to Claim 3, 10 which consists in heating the acetone solvate form A between 100 and 110*C under vacuum or nitrogen sweeping, preferably for at least 9 hours, and then returning to ambient temperature.
17. - Method for preparing the anhydrous form C according to Claim 4, by maturation of the acetone solvate form A, or of the anhydrous form B, in water, 15 followed by drying up to approximately 50'C and then maintaining at ambient temperature at a relative humidity of less than 5%.
18. - Method for preparing the anhydrous form D according to Claim 5, by maturation, at ambient temperature, of the acetone solvate form A in ethanol and drying under nitrogen or under vacuum. 20 19. - Method for preparing the anhydrous form D according to Claim 5, by crystallization, at ambient temperature, of the acetone solvate form A from an oil, followed by rinsing with an alkane.
20. - Method for preparing the anhydrous form D according to Claim 5, by crystallization of a solution of 4 -acetoxy-2a-benzoyloxy-5p,20-epoxy-1-hydroxy 25 7p,1OP-dimethoxy-9-oxotax-ll-en-13a-yI (2R,3S)-3-tert-butoxycarbonylamino 2 -hydroxy-3-phenylpropionate in a mixture of Polysorbate 80, pH 3.5, ethanol and water (preferably, a 25/25/50 mixture) for approximately 48 hours at ambient temperature.
21. - Method for preparing the anhydrous form E according to Claim 6, by 30 maturation of the acetone solvate form A in ethanol so as to intermediately form an ethanolic form which is subsequently desolvated under nitrogen sweeping or by WO 2009/115655 PCTIFR2009/000042 10 heating at approximately 100 0 C for 2 hours and then returning to ambient temperature.
22. - Method for preparing the anhydrous form F according to Claim 7, by desolvating the ethanol/water heterosolvate at 120'C under a nitrogen atmosphere for 5 24 hours and then maintaining at a relative humidity of 0% at ambient temperature.
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| FR0800243 | 2008-01-17 | ||
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